This study investigated factors associated with the development of human herpesvirus (HHV)-6 encephalitis. Among 111 enrolled subjects, 12 patients developed central nervous system (CNS) dysfunction. CNS dysfunction in four patients was found to have no association with HHV-6. The remaining eight patients displayed HHV-6 encephalitis (n ¼ 3), limbic encephalitis (HHV-6 DNA in cerebrospinal fluid was not examined; n ¼ 3) or CNS dysfunction because of an unidentified cause (n ¼ 2). Realtime PCR showed CNS dysfunction in the latter eight patients, which developed concomitant with the appearance of high plasma levels of HHV-6 DNA (X10 4 copies/ml). Overall, eight of the 24 patients with high-level HHV-6 DNA developed CNS dysfunction, whereas no patients developed CNS dysfunction potentially associated with HHV-6 infection if peak HHV-6 DNA was o10 4 copies/ ml. We next analyzed plasma concentrations of IL-6, IL-10 and tumor necrosis factor-a among patients who displayed high-level plasma HHV-6 DNA and found elevated IL-6 concentrations preceding HHV-6 infection in patients who developed CNS dysfunction. (Mean ± s.d.: 865.7 ± 1036.3 pg/ml in patients with CNS dysfunction; 56.5±192.9 pg/ml in others; P ¼ 0.01). These results suggest that high-level HHV-6 load is necessary for the development of HHV-6 encephalitis, and systemic inflammatory conditions before HHV-6 infection form the preparatory conditions for progression to encephalopathy.

In this retrospective analysis using the Transplant Registry Unified Management Program, we identified 145 patients with human herpesvirus (HHV)-6 encephalitis among 6593 recipients. The cumulative incidences of HHV-6 encephalitis at 100 days after transplantation in all patients, recipients of bone marrow or PBSCs and recipients of cord blood were 2.3%, 1.6% and 5.0%, respectively. Risk factors identified in multivariate analysis were male sex, type of transplanted cells (relative risk in cord blood transplantation, 11.09, P o0.001; relative risk in transplantation from HLA-mismatched unrelated donor, 9.48, P o0.001; vs transplantation from HLA-matched related donor) and GvHD prophylaxis by calcineurin inhibitor alone. At 100 days after transplantation, the overall survival rate was 58.3% and 80.5% among patients with and without HHV-6 encephalitis, respectively (P o 0.001). Neuropsychological sequelae remained in 57% of 121 evaluated patients. With both foscarnet and ganciclovir, full-dose therapy (foscarnet ⩾ 180 mg/kg, ganciclovir ⩾ 10 mg/kg) was associated with better response rate (foscarnet, 93% vs 74%, P = 0.044; ganciclovir, 84% vs 58%, P = 0.047). HHV-6 encephalitis is not rare not only in cord blood transplant recipients but also in recipients of HLA-mismatched unrelated donors. In this study, development of HHV-6 encephalitis was associated with a poor survival rate, and neurological sequelae remained in many patients.

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Our results suggest that differences in fatal CHD rates between Japanese and Americans were not as large as suggested by vital statistics when events were validated and sudden deaths were included.

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